Background: Chronic hepatitis B (CHB) virus is a major global health concern, often progressing to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Genetic polymorphisms in SOCS3 and SLC29A1 have been implicated in disease susceptibility. However, their roles in the Egyptian population remain underexplored. Aim: This study aims to investigate the association of SOCS3 (rs4969168, rs4969170) and SLC29A1 (rs760370) polymorphisms with the progression of hepatitis B virus (HBV)-related liver diseases in a group of Egyptian patients. Subjects and Methods: The study was conducted on 50 healthy controls, 50 CHB patients, and 50 LC patients. Genomic DNA was extracted and analyzed for polymorphisms using quantitative real-time PCR. Routine laboratory tests and clinical assessments were performed. Statistical analysis was used to identify any associations between genetic polymorphisms, immune response, and clinical outcomes. Results: The SLC29A1 rs760370 AA genotype was more prevalent in CHB (70%) and LC (86%) patients than in controls (24%) (P < 0.001). Carriers of the A allele had higher odds for CHB (OR = 20.417) and LC (OR = 25.083). The SOCS3 rs4969168 GG genotype was associated with CHB (50%) and LC (82%) compared to controls (14%) (P < 0.001), with increased susceptibility (OR = 6.296 and 22.034). The SOCS3 rs4969170 GG genotype had the highest odds for CHB (OR = 279.0) and LC (OR = 1302.0). Conclusion: This study identifies SOCS3 and SLC29A1 gene polymorphisms as major genetic determinants in HBV-related liver disease progression in Egyptian patients, highlighting their use as potential biomarkers for HBV-related risk assessment.